Carboxylic acid derivatives of sub-



United States Patent Ofitice 3,064,003 Patented Nov. 13, 1962 The present invention relates to new and novel compounds of the formula I Ra wherein R is hydrogen, aryl or lower alkyl, R is hydrogen or lower alkyl, and R is lower alkyl, and to a method of producing such compounds.

The term low alkyl as used in the specification and in the claims refers to branched and straight chain aliphatic groups having 1 to 6 carbon atoms.

The compounds of this invention have interesting pharmacological activity as analgesics, sedatives and antiinfiammatory agents. In use, they may be formulated with conventional pharmaceutical carriers to form such typical dosage units as tablets, capsules, solutions, suspensions, suppositories and the like.

It has now been found that the new and novel compounds of this invention may be prepared by the reaction of a compound of the formula wherein R R and R are as described hereinabove and R is a lower alkyl group with a molar excess of a base, such as sodium hydroxide, potassium hydroxide and the like, at a temperature of about 50 C. to about 100 (3., followed by neutralization of the reaction mixture with a mineral acid, such as hydrochloric acid, sulfuric acid and the like, at a temperature of less than C. The reactionis normally carried out in aqueous solution. The product is purified by crystallization.

The starting materials of the above formula may be prepared by the following reaction sequence:

First, a substituted 4-thiazolidinone of the formula wherein M is an alkali metal is prepared by the reaction of a nitrile of the formula H R40 0 CC|JO N R1 with a mercapto ester of the formula wherein R is lower alkyl, in the presence of an aliphatic alcohol having 1 to 6 carbon atoms and an alkali metal, as described in my application entitled Substituted 4- 'I'hiazolidinones and Process Therefor, filed concurrently herewith, now copending application Serial No. 93,301 filed March 6, 1961.

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wherein X is halogen, as described in my application entitled Substituted 4-Thiazolidinones and Process Therefor, filed concurrently herewith, now copending application Serial No. 93,318 filed March 6, 1961.

The following example is included in order further to illustrate the present invention:

EXAMPLE 2-Carboxymethylene-3-Methyl-4-Thiazolidinone 20 g. (0.1 mole) 2-carbethoxymethylene-3-methyl-4- thiazolidinone are mixed with ml. 2 N NaOH, the mixture is heated to 60-70 C. and maintained at this temperature for 5 minutes, whereupon a complete solution takes place. The solution is then cooled to l0 C. and, after 10 minutes, is filtered. To the filtrate are slowly added 50 ml. 2 N HCl with vigorous agitation of the mixture and cooling to maintain the temperature at 10 C. The mixture is allowed to stand at --10 C. for 30 minutes and thereafter is filtered. The crystals are washed successively with water, ethanol and ether and recrystallized from dioxan to yield 14 g. (82%) of 2-carboxymethylene-3 methyl-4 thiazolidinone as colorless crystals, melting point 176 C. dec.

Analysis-Cale: C, 41.60; H, 4.08; N, 8.09; S, 18.52. Found: C, 41.68; H, 3.93; N, 8.11; S, 18.00.

By a similar procedure other carboxylic acid derivatives of substituted 4-thiazolidinones may be prepared, for example 2-(u-carboxybenzylidene) 3-methyl-4-thiazolidinone, 2- a-carboxyethylidene) -3-methyl-4-thiazolidinone, 2-car boxymethylene-3-methyl-5-methyl-4-thiazolidinone, 2 (u carboxyethylidene) 3 ethyl-S-methyl- 4-thiazolidinone, and the like.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patent is:

1. A compound of the formula References Cited in the file of this patent UNITED STATES PATENTS Knot-t Apr. 24, 1956 Sheehan Apr. 26, 19 60 OTHER REFERENCES Karrer: Organic Chemistry (Elsevier), page 212 (1950). 

1. A COMPOUND OF THE FORMULA 